Abstract & Commentary

Chronicling the ominous rise of new C. diff strain

Evidence is accumulating, none of it good

Synopsis: Clostridium difficile-associated disease (CDAD) is increasing in incidence and severity, and is appearing in patients even in the absence of recent hospitalization or antimicrobial use.

Source: CDC. Severe Clostridium difficile-associated disease in populations previously at low risk—four states, 2005. MMWR 2005; 54: 1,201-1,205.

Clostridium difficile-associated diarrhea (CDAD) is most often nosocomially acquired and usually affects older, sicker patients. The incidence of hospital discharges with a diagnosis of CDAD in the United States increased by 26% between 2000 and 2001.1 At the same time, some evidence suggests that, in some areas, CDAD has become more severe and more recalcitrant to treatment. In a demonstration of the apparently increasing and expanding danger of CDAD, the CDC now has reported on the occurrence of severe CDAD in individuals not normally considered at risk.

Their investigation was initially precipitated by the report of cases of severe CDAD in otherwise healthy patients with minimal or no exposure to health care facilities. One of these was a 31-year-old woman who presented during the 14th week of pregnancy with a three-week history of intermittent diarrhea due to C. difficile, which had significantly worsened in the last three days. She had received trimethoprim-sulfamethoxazole for treatment of a urinary tract infection approximately three months previously. She relapsed after each of two courses of therapy and, despite a subtotal colectomy, died. A second patient, a previously healthy 10-year-old girl, who had received no antimicrobials in the preceding year, developed CDAD with 14 liquid stools per day. She responded to intravenous fluids and metronidazole.

A request for voluntary reports from several states resulted in the identification of 10 peripartum (within four weeks before or after delivery) and 23 community-acquired cases from four states. In 4 cases, there had been apparent transmission from close contacts. Three (9%) of the 23 patients had received three or fewer doses of antibiotics. There had been no antimicrobial exposure in eight (24%), and three of the eight without antibiotic exposure were close contacts of index cases.

Commentary by Stan Deresinski, MD, FACP, clinical professor of medicine, Stanford (CA) University; and associate chief of infectious diseases, Santa Clara Valley (CA) Medical Center.

This experience has emerged at the same time that significant outbreaks of severe health care-associated CDAD have occurred in North America and Europe. An epidemic in Montreal and southern Quebec, beginning in 2002, resulted in 14,000 reported cases between 2003 and 2004, with incidence rates five times greater than the historical average.2 At the same time, at a university hospital in Quebec, the 30-day crude mortality of patients with CDAD increased from 4.7% to 13.8%. A comparable experience in Sweden has been reported,3 and outbreaks have occurred in recent years in multiple states of the United States. Some evidence indicate that at least some of these outbreaks, as well as the frequently associated increased severity of disease, may be the result of the emergence of hypervirulent strains of C. difficile.

The damage to colonic mucosa in patients with CDAD is the result of the production of exotoxins. Genes encoding toxins A (tcdA) and B (tcdB) are located within PaLoc, a 19.6 kb pathogenicity locus carried on the chromosome of pathogenic strains of C. difficile. These toxins are coregulated by two genes, tcdC and tcdD. The latter, tcdD, is a positive regulator, while the former, tcdC, is strongly expressed during logarithmic growth of the organism, resulting in transcriptional suppression of the genes encoding these toxins. Transcription of the toxin genes is, in contrast, increased during stationary growth. Both toxins A and B translocate to the cytosol and inactivate small GTP-binding proteins, such as Rho, resulting in disruption of the actin cytoskeleton and cell death.4 Some strains also encode a binary toxin, similar to the iota toxin of Clostridium perfringens, whose pathogenic role remains unproven. One component of this toxin is important for binding to the cell membrane and intracellular translocation while the other causes cell death by disruption of actin filament assembly.

Several typing systems are generally used in the examination of strains of C. difficile. These include ribotype determination by restriction endonuclease analysis and pulsed-field gel electrophoresis. In addition, toxinotype is determined by determination of polymorphisms in PaLoc. Some of the recent outbreaks of severe CDAD have been associated with the emergence of a strain designated ribotype 027, toxinotype III. An additional feature common to strains implicated in some of the outbreaks has been the presence of an 18-bp deletion, the negative regulator, tcdC, probably accounting for the increased toxin production by these strains.

Patients affected during the epidemic in the province of Quebec had an attributable mortality of 6.9%. Factors identified as risks for CDAD, some cases of which were community acquired, were prior receipt of fluoroquinolones (82% of isolates were fluoroquinolone-resistant) or cephalosporins.5 In addition to toxins A and B, 84% of isolates bore the genes for the binary toxin, as well as deletions in tcdC. Peak in vitro toxin A and toxin B production by this dominant strain was 16- and 23-fold higher than that of historic strains, presumably as a consequence of the deletions in tcdC.2

The predominant strain among isolates from recent outbreaks in six U.S. states were of the same ribotype as the predominant Canadian strain, and belonged to toxinotype III.6 They also contained genes encoding binary toxin and had 18-bp deletions in tcdC. Organisms with these characteristics were resistant to gatifloxacin and moxifloxacin, and most were resistant to clindamycin.

Thus, the evidence of emergence of a dominant strain as a cause of severe CDAD, often in epidemic fashion, continues to accumulate. Complicating matters for the clinician is the fact that CDAD may become increasingly recalcitrant to treatment, especially with metronidazole. This is occurring despite the fact that detection of in vitro resistance to metronidazole has been quite rare. This may, also, however, be changing. In Montreal, while only 6% of pre-epidemic C. difficile isolates had an MIC > 1 mcg/mL, 38% of epidemic isolates (P < 0.001) had an MIC > 1 mcg/mL.7 In addition, investigators in Spain recently reported a 1.1% prevalence of homogenously expressed metronidazole resistance. However, 32% expressed heterogeneous resistance as defined by the presence of colonies within the zone of inhibition in an E-test.8

All of these reports clearly demonstrate the need for implementation of proactively aggressive interventions aimed at preventing CDAD. While many of the following recommendations apply to inpatient settings, the increasing risk of severe community-acquired CDAD in patients without known risk factors (including no antibiotic exposure) must also be taken into account.


  • Monitor for changes in incidence and severity of CDAD.
  • Upon identification of a case, discontinue antibiotics, if possible, and treat with orally administered metronidazole or, in severe cases, vancomycin.9
  • Prevent transmission by strictly enforced contact precautions, barrier nursing where appropriate, prohibition of use of shared patient bathrooms, enhanced environmental cleaning with sporicidal agents (e.g., diluted bleach), and hand washing with soap and water (not alcohol).
  • Contact precautions should consist of: use of a single room or of cohorting (although variable antibiotic resistance and virulence would argue against this); use of gloves and gowns on entering the patient’s room; and exclusive use (or cleaning between patients) of blood pressure cuffs, stethoscopes, and other patient care equipment.
  • Institutional implementation of effective antibiotic stewardship, with elimination of unnecessary antibiotics use, especially of implicated agents.
  • Reduction of unnecessary use of proton pump inhibitors (identified in other studies as a risk factor for CDAD).


  1. McDonald CL, et al. Increasing incidence of Clostridium difficile-associated disease in U.S. acute care hospitals, 1992-2001 (Abstract). In: Proceedings of the 14th Annual Scientific Meeting of the Society for Healthcare Epidemiology of America, Philadelphia; April 2004.
  2. Warny M, et al. Toxin production by an emerging strain of Clostridium difficile-associated with outbreaks of severe disease in North America and Europe. Lancet 2005; 366:1,079-1,084.
  3. Karlstrom O, et al. A prospective nationwide study of Clostridium difficile-associated diarrhea in Sweden: The Swedish C. difficile Study Group. Clin Infect Dis 1998; 26:141-145.
  4. Voth DE, Ballard JD. Clostridium difficile toxins: Mechanism of action and role in disease. Clin Microbiol Rev 2005; 18:247-263.
  5. Loo VG, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with morbidity and mortality. N Engl J Med 2005. Epub ahead of print.
  6. McDonald LC, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 2005. Epub ahead of print.
  7. Labba A, et al. In vitro activities of 11 antibiotics against Clostridium difficile isolates recovered in a Montreal hospital during 2 different periods. Abstract E-1436. 45th ICAAC, Washington DC; December 2005.
  8. Pelaez T, et al. Clostridium difficile with heterogeneous resistant to metronidazole: Prevalence in the clinical setting and critical assessment of diagnostic methods. Abstract C2-466. 45th ICAAC, Washington DC; December 2005.
  9. Aslam S, et al. Treatment of Clostridium difficile-associated disease: Old therapies and new strategies. Lancet Infect Dis 2005; 5:549-557.